The Role of Cytomegalovirus in Prostate Cancer Incidence and Mortality

Prostate cancer is one of the most common cancers in men with over 350 000 prostate cancer deaths reported worldwide every year. Current risk stratification models are insufficient to predict prostate cancer and prostate cancer death. New biomarkers are needed to identify those at increased risk of lethal prostate cancer. Cytomegalovirus (CMV) infection is common in the healthy prostate epithelium and promotes cell proliferation and viability in prostate cancer. Analyzing matched serum and tissue samples from post-mortem donors (n=41) and prostate cancer patients (n=40), we report that CMV seropositivity predicts high CMV abundance in prostate tissue. We studied if CMV seropositive men had increased prostate cancer incidence and cancer mortality in the European Prospective Investigation of Cancer (EPIC)–Norfolk population-based cohort study. CMV IgG serostatus was determined between 1993 and 2000 in 7,655 men aged 40-81 years, of which 57% were CMV seropositive. Study participants were followed for 18±6.0 years (mean±SD). We used Cox proportional hazard models, adjusted for age and potential confounders to estimate hazard ratios (HR) with 95% confidence intervals (CI). CMV serostatus was not associated with prostate cancer incidence (adjusted HR 1.03, 95% CI 0.89-1.19, p=0.687, 138,652 person-years). However, among prostate cancer patients, CMV seropositivity was associated with increased risk of prostate cancer-associated mortality (adjusted HR 2.26, CI 95% 1.02-4.99, p=0.044, 4639 person-years), with 25% of seropositive and 18% of seronegative prostate cancer patients dying from their disease during follow up. These results show that CMV seropositivity is associated with increased risk of prostate cancer death and suggest that CMV infection may contribute to prostate cancer lethality. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by grants from the Swedish Research Council (D0761801), the Swedish Cancer Society (19 0452 Pj, 22 2358 Pj), the Swedish Foundation for Strategic Research (SB16-0014) and Knut och Alice Wallenbergs Stiftelse (2018.0063). The PCBN biobank is supported by the Department of Defense Prostate Cancer Research Program Award No W81XWH-14-2-0182, W81XWH-14-2-0183, W81XWH-14-2-0185, W81XWH-14-2-0186, and W81XWH-15-2-0062 Prostate Cancer Biorepository Network. J.C was supported by the Clinical Scientist Training Program at Karolinska Institutet. E.GK was supported by the NIHR Cambridge Biomedical Research Centre (NIHR203312). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The regional ethics committee of Sweden gave ethical approval (2010/313-31/3) of this work (2010/313-31/3). The local institutional review board at Memorial Sloan Kettering Cancer Center, New York, USA gave ethical approval for this work (Protocol #15-025). The Norwich Local Research Ethics Committe and Waveney NHS Research Governance Commitee gave ethical approval for this work (REC ref: 98CN01; 05/Q0101/191 and 2005EC07L). The Swedish Ethical Review Authority gave ethical approval for this work (2021-00457 and 2022-00965-02). See ethics statement in methods section for further details. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.